The development of effective sustained release compositions containing complex biologically active molecules such as growth hormones requires the identification of systems which are biocompatable and do not interfere or interact with the activity of these molecules.
Recent developments in the area of administration of growth hormones include those described by S. L. Davis, et al., in The Journal of Dairy Science, Vol. 66, No. 9, pp 1980-1981 (1983) which describes the use of beeswax implants for the administration of the growth hormone oGH. A cholesterol matrix delivery system for the sustained release of macromolecules, including a variety of growth hormones, is described in U.S. Pat. No. 4,452,775. Injectable sustained release compositions include biodegradable polymer microcapsules containing aqueous solutions of polypeptides which are described in European Patent Application 81305426.9; a crystalline carbohydrate nanosphere matrix described by U. Schroder, J. Immunological Methods, 70, pp 127-132 (1984); prolonged release nonaqeuous compositions of polypeptides which are preferably associated with metals or metal compounds which may additionally contain antihydration agents dispersed in biocompatible oils, which are described in European Patent Application 85870135.2, published Apr. 4, 1986. Pending Application for United States Letters Patent of S. Cady, R. Fishbein, U. Schroder, H. Erickson and B. Probasco, Ser. No. 830,158, filed Mar. 20, 1986, and pending Application for United States Letters Patent of W. Steber, R. Fishbein and S. Cady, Ser. No. 895,608, filed Aug. 11, 1986, describe sustained release compositions of biologically active molecules utilizing water dispersible carbohydrate polymer-aqueous systems and solid fat and/or wax-oil systems respectively . Systained release compositions of proteins and enzymes coupled to polyethylene and polypropylene glycols are described in U.S. Pat. No. 4,179,337; and European Patent Application 85301032.0, which describes a coupled enzyme, urokinase. A review of soluble polymer-enzyme adducts by A. Abuchowski and F. Davis is presented in Chapter 13 of Enzymes as Drugs, John Wiley and Sons (1981). Analytical and separation methods for use in biochemistry have been developed utilizing affinity chromatography which takes advantage of specific naturally occurring biological affinities such as antigen-antibody attraction, which are imparted to the chromatography adsorbant by covalently bonding the binding component to an activated matrix on a fixed support such as glass beads. The availability of affinity chromatography media which may be activated to covalently bond biologically active macromolecules has resulted in research such as that reported by N. Sinha and A. Light in The Journal of Biological Chemistry, Vol. 250, No. 22, pp 8624-8629, (1975), which describes the refolding of reduced trypsinogen and trypsin immobilized on agarose beads upon reoxidation.
It is an object of this invention to provide sustained release compositions comprising adducts of growth hormones, somatomedins, growth factors and biologically active fragments thereof, convalently bonded to biologically compatable activated polysaccharides which are suitable for parenteral administration.
It is another object of this invention to provide a method for increasing and maintaining increased levels of growth hormones in the blood of treated animals and humans for extended periods of time and obtaining beneficial effects such as increasing weight gains, increasing milk production in lactating animals, increasing growth rate, increasing feed efficiency, increasing muscle size, decreasing body fat and improving lean meat to fat ratio by parenteral administration of the compositions of the invention.